Improving Molecular Understandings of mCRC

Howard S. Hochster, MD, FACP: I think that our appreciation of how to treat colon cancer in 2019 has evolved a little bit over the last couple of years in 2 different ways. One of them is understanding the molecular subsets that require special kinds of therapies, and the other is more or less an anatomic basis looking at right-sided colon cancer versus left-sided colon cancer. And it’s funny that after all this interest in molecular biology and all these studies and different classifications, it comes down to something as obvious as right sided or left sided. Even our surgeons and pathologists can do that by looking at the colon. It’s a very interesting paradox.

Today it’s very important that every patient who has colon cancer, especially metastatic colon cancer, undergo a series of molecular tests to help direct their therapy. So the first one that we really understood the best was the RAS mutation testing, and we know that is not so much prognostic but predictive for the use of anti-EGFR epidermal growth factor receptor antibodies. And those patients who have RAS wild-type disease—and that’s both KRAS and NRAS—will benefit from use of these antibodies if they’re wild-type. If they have a mutation, then you shouldn’t use these antibodies, so that’s more or less 50-50 of all colon cancer. So, we’ve taken a drug that we use across the board and selected the better half of the patient population to receive it, so it’s actually improved the response rate with these drugs by doubling it.

So the RAS is the first thing, and then we know now about BRAF mutations. Those are very much prognostic. We know those patients do much worse, and we can see those mutations in right-sided colon cancer in younger patients, and that’s a particularly ominous finding. So we want to be aware of that earlier, so we can try to treat patients more aggressively with 3-drug combinations plus antibodies. So that’s the second important molecular subset.

And then there are a couple of other ones that we’ve become more aware of and we need to also look for. Data have emerged on HER2-overexpressing colon cancer. It’s a small subset, 4% to 5%, but they’re all RAS wild-type. So, if you take the RAS testing first and then you test for HER2 staining for people who are wild-type, now you’re up to 8% to 10%, which is a more reasonable number. And those patients may very well benefit from the same kind of anti-HER2 therapies that we use in breast cancer. And I’d like to call people’s attention to the SWOG 1613 [S1613] study, which is comparing a standard second-line therapy to anti-HER2 therapy for this patient population. That study is accruing now. It’s a randomized study and it’s a very important one.

And finally, we know that there are certain fusion proteins now in colon cancer, like the ones in lung cancer, that are more common. And the main one is TRK or the TRK family, NTRK. In particular, that’s about 3% to 4% of colon cancer. And those patients can benefit from a specific inhibitor today.

I want to also call people’s attention to the patients who have microsatellite instability. This is a situation that we’ve come to understand, mainly because of colon cancer in families with Lynch syndrome. From the finding of this kind of colon cancer that runs in the family—understanding the molecular biology—we’ve understood that these are people who have deficiencies in mismatch repair enzymes that can be inherited. And that was interesting but didn’t have many therapeutic implications until a couple years ago, when the link was made between having a microsatellite unstable tumor and benefiting from immunotherapy. So that group of patients can really benefit from the anti-PD-1 drugs, unlike the other 90% of patients with colon cancer. And so we need to identify those patients and make sure they get directed to the appropriate trials or approved usage of anti-PD-1 antibodies.

Transcript Edited for Clarity

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Transcript:

Howard S. Hochster, MD, FACP: I think that our appreciation of how to treat colon cancer in 2019 has evolved a little bit over the last couple of years in 2 different ways. One of them is understanding the molecular subsets that require special kinds of therapies, and the other is more or less an anatomic basis looking at right-sided colon cancer versus left-sided colon cancer. And it’s funny that after all this interest in molecular biology and all these studies and different classifications, it comes down to something as obvious as right sided or left sided. Even our surgeons and pathologists can do that by looking at the colon. It’s a very interesting paradox.

Today it’s very important that every patient who has colon cancer, especially metastatic colon cancer, undergo a series of molecular tests to help direct their therapy. So the first one that we really understood the best was the RAS mutation testing, and we know that is not so much prognostic but predictive for the use of anti-EGFR epidermal growth factor receptor antibodies. And those patients who have RAS wild-type disease—and that’s both KRAS and NRAS—will benefit from use of these antibodies if they’re wild-type. If they have a mutation, then you shouldn’t use these antibodies, so that’s more or less 50-50 of all colon cancer. So, we’ve taken a drug that we use across the board and selected the better half of the patient population to receive it, so it’s actually improved the response rate with these drugs by doubling it.

So the RAS is the first thing, and then we know now about BRAF mutations. Those are very much prognostic. We know those patients do much worse, and we can see those mutations in right-sided colon cancer in younger patients, and that’s a particularly ominous finding. So we want to be aware of that earlier, so we can try to treat patients more aggressively with 3-drug combinations plus antibodies. So that’s the second important molecular subset.

And then there are a couple of other ones that we’ve become more aware of and we need to also look for. Data have emerged on HER2-overexpressing colon cancer. It’s a small subset, 4% to 5%, but they’re all RAS wild-type. So, if you take the RAS testing first and then you test for HER2 staining for people who are wild-type, now you’re up to 8% to 10%, which is a more reasonable number. And those patients may very well benefit from the same kind of anti-HER2 therapies that we use in breast cancer. And I’d like to call people’s attention to the SWOG 1613 [S1613] study, which is comparing a standard second-line therapy to anti-HER2 therapy for this patient population. That study is accruing now. It’s a randomized study and it’s a very important one.

And finally, we know that there are certain fusion proteins now in colon cancer, like the ones in lung cancer, that are more common. And the main one is TRK or the TRK family, NTRK. In particular, that’s about 3% to 4% of colon cancer. And those patients can benefit from a specific inhibitor today.

I want to also call people’s attention to the patients who have microsatellite instability. This is a situation that we’ve come to understand, mainly because of colon cancer in families with Lynch syndrome. From the finding of this kind of colon cancer that runs in the family—understanding the molecular biology—we’ve understood that these are people who have deficiencies in mismatch repair enzymes that can be inherited. And that was interesting but didn’t have many therapeutic implications until a couple years ago, when the link was made between having a microsatellite unstable tumor and benefiting from immunotherapy. So that group of patients can really benefit from the anti-PD-1 drugs, unlike the other 90% of patients with colon cancer. And so we need to identify those patients and make sure they get directed to the appropriate trials or approved usage of anti-PD-1 antibodies.